The essential function of the heart is to pump blood to the body. The major cellular constituents of the heart are cardiac fibroblasts, cardiomyocytes, endothelial cells, and vascular smooth muscle cells. During cardiogenesis, some cardiomyocytes are further differentiated into the specialized conduction system consisting of the sinus node, AV node, and HIS-Purkinje system. Cardiomyocytes and the specialized conduction system are the electrically active cells of the heart. The heart is both an electrical and a mechanical organ in which cellular membrane potentials control initiation of mechanical contraction followed by relaxation. The coordinated electrical activity results in mechanical contraction and the pump function of the heart. Under normal conditions, heartbeats are initiated by depolarizing pacemaker currents in the sinus node that then depolarize sequential neighboring cardiomyocytes in the atrium resulting in a depolarization wavefront across the atrium. The wavefront of depolarization then depolarizes as the AV node which sequentially depolarizes the His-Purkinje system and then the ventricular cardiomyocytes. Electrical depolarization initiates cardiac contraction of cardiomyocytes. Cellular ionic currents then result in electrical repolarization of each cell type and relaxation of cardiomyocytes. Repolarized cells are then available to become activated again with a depolarization wavefront for the next heart beat that is initiated by the sinus node.
The depolarization wavefront is dependent on cellular ionic currents with the inward sodium current being the dominant depolarization current and cell-to-cell connections know as gap junctions that allow transmission of electrical currents between cells. The principal gap junction proteins are connexins 40 and 43.
Disease states can result in slowing of the conduction velocity of the depolarization wavefront. Reentry is the most common mechanism of cardiac arrhythmias. The wavelength theory of arrhythmias suggests that reentry is more likely to occur when conduction velocity slows or refractoriness of cell is decreased. Additionally, disease states may result in cardiac fibrosis and dilatation of the atrium and ventricles. Areas of fibrosis may slow or block the depolarization wavefront. Dilatation of cardiac chambers prolongs the time required to depolarize each chamber and makes reentry more likely.
Treatment options for cardiac arrhythmias consists of antiarrhythmic drugs, ablation, and device therapy such as pacemakers and defibrillators. Most efforts in treating cardiac arrhythmias are to prolong repolarization and refractoriness to make reentry less likely. These include antiarrhythmic drugs such as amiodarone, sotalol, and dofetilide. Other efforts to treat cardiac arrhythmias consist of using ablation to block part of a circuit of reentry. Ablation and consists of destruction of cardiomyocytes with heating or cooling of tissue. Cardiomyocytes are then replaced with fibroblasts which are not electrically conductive once the tissue has healed. Correction of conduction delays by improving conduction velocity with Connexin gene transfer is another potential approach to treat arrhythmias (Igarashi, et al., Circulation. 2012; 125: 216-225), but this approach remains in early stages of research.
Disease states result in slowing of conduction velocity and dilation of cardiac chambers results in larger distances for wavefronts of depolarization to travel. The summation of slower conduction velocity and larger distances result in substantial conduction delays when compared to normal physiology. Additionally, disease states are often associated with blocks in the specialized conducting system such as the left bundle of the Purkinje system. Loss of the normal synchronization of electrical activation results and what is known as dyssynchrony. Dyssynchrony of electrical activation results in dyssynchrony of the mechanical activation and less efficient contraction of the heart. Correction of conduction delays that improve synchrony of electrical activation and subsequently mechanical activation may improve cardiac function. This is the principal behind resynchronization therapy that is currently performed using pacemakers with multiple pacing electrodes.
Conduction abnormalities can deprive the heart of normal functioning. They can, for example, disrupt normal synchrony and produce any of a number of different conduction disorders. Cardiac arrhythmias are a leading cause of morbidity in the Western hemisphere. The risk of developing malignant ventricular tachyarrhythmias is associated with the extent of myocardial injury and is believed to be the primary cause of approximately 50% of all cardiovascular deaths. Bradycardia and heart block, which can result from the normal aging process, further contribute to the morbidity associated with cardiac arrhythmias and result in permanent implantation of over 160,000 pacemakers annually in the United States. Atrial fibrillation is the most common cardiac arrhythmia and is characterized by rapid, irregular, uncoordinated depolarizations of the atria with no definite P waves. It can occur as a result of numerous different pathophysiological processes in the two upper chambers (atria) of the heart.
Several techniques or hypotheses have been deployed in the field for stabilizing cardiac arrhythmia. Most, however, are impractical or require a critical surgical procedure. In some instances, especially where the condition arises from a conduction disturbance that is due to ischemia, only radical options, such as surgery, are available. However, even surgical techniques can fall well short of the therapeutic goal of restoring cardiac function to the patient. For example, although a surgical procedure known as “maze” was designed to eliminate atrial fibrillation permanently, it gave rise to a number of complications. In the maze procedure, incisions are made with a scalpel in the walls of the atria in order to block electrical impulse conduction in a direction crosswise to the incisions, i.e., by interruption of the local tissue continuity. As a result of subsequent scarring, these electrical blocks acquire a permanent, irreversible character. However, the long duration of the operation creates a considerable risk of damage to the heart muscle.
Tissue engineering techniques generally involve transplanting cells that can imitate certain cardiac functions in to cardiac tissue in order to effect myocardial repair. One proposed technique attempts to establish electrical coupling between cardiomyocytes and recombinant cells that have been genetically engineered to express a connexin protein, such as connexin 43. See You, et al., Nano Lett. 2011, 11, 3643-3648.
Various antiarrhythmic drugs also have the potential to restore normal heart rhythm. These include quinidine, procainamide, disopyramide, flecainide, propafenone, dofetilide, ibutilide, azimilde, amiodarone, and sotalol. However, such medications are effective in only 30-60% of patients and in any event generally lose effectiveness over time. In addition, some antiarrhythmic drugs have the potential to produce serious side effects.
Anti-arrhythmic drugs and radiofrequency catheter ablation are presently the most commonly-used techniques for controlling atrial fibrillation. Radiofrequency ablation uses irreversible destruction of atrial tissue to attempt to block circuits of atrial fibrillation. The procedure is highly invasive and has significant procedural risk, and the results have substantial variability in clinical practice.
Correction of conduction abnormalities may be antiarrhythmic by improving synchrony of depolarization and making reentry more difficult to occur. Correction of conduction abnormalities may be therapeutic for restoration of synchrony and improve cardiac function. The approach of improving conduction may have advantages over antiarrhythmic drug therapy and ablation therapy. New methodologies that are at least partially curative, less invasive that existing techniques, reversible, and preferably tunable could represent viable treatment alternatives for thousands of affected individuals.